Tiam1 Overexpression Potentiates Heregulin-induced Lymphoid Enhancer Factor-1/β-Catenin Nuclear Signaling in Breast Cancer Cells by Modulating the Intercellular Stability

Liana Adam, Ratna K. Vadlamudi, Pierre McCrea, Rakesh Kumar

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Heregulin-β1 (HRG) promotes motility, scattering, and invasiveness of breast cancer cells. Tiam1, a newly identified guanine nucleotide exchange factor, has been shown to inhibit or promote cell migration in a cell type-dependent manner. In this study, we identified Tiam1 as a target of HRG signaling. HRG stimulation of breast cancer epithelial cells induced the phosphorylation and redistribution of Tiam1 to the membrane ruffles and the loosening of intercellular junctions. In addition, HRG-mediated scattering of breast epithelial cells was accompanied by stimulation of tyrosine phosphorylation and redistribution of β-catenin from the cell junctions to the cytosol and, finally, entry into the nucleus. Decompaction of breast cancer epithelial cells by HRG was accompanied by a transient physical association of the tyrosine-phosphorylated β-catenin with the activated human epidermal growth factor receptor 2 and subsequent nuclear translocation of β-catenin, as well as β-catenin-dependent transactivation of T-cell factor·lymphoid enhancer factor-1. All of these HRG-induced phenotypic changes were regulated in a phosphatidylinositol-3 kinase-sensitive manner. HRG-induced cellular ruffles, loss of intercellular adhesiveness, and increased cell migration could be mimicked by overexpression of a fully functional Tiam1 construct. Furthermore, ectopic expression of Tiam1 or of an active β-catenin mutant led to potentiation of the 13-catenin-dependent T-cell factor·lymphoid enhancer factor-1 transactivation and invasiveness of HRG-treated cells. We also found preliminary evidence suggesting a close correlation between the status of Tiam1 expression and invasiveness of human breast tumor cells with the degree of progression of breast tumors. Together, these findings suggest that HRG regulate Tiam1 activation and lymphoid enhancer factor/β-catenin nuclear signaling via phosphatidylinositol-3 kinase in breast cancer cells.

Original languageEnglish (US)
Pages (from-to)28443-28450
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number30
DOIs
Publication statusPublished - Jul 27 2001

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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